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T cells can mount attacks against many SARS-CoV-2 targets–even on new virus variant

New LJI research gives detailed look at vulnerable sites on the novel coronavirus–beyond the receptor binding domainCredit: NIAID LA JOLLA–A

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New LJI research gives detailed look at vulnerable sites on the novel coronavirus–beyond the receptor binding domain

LA JOLLA–A new study led by scientists at La Jolla Institute for Immunology (LJI) suggests that T cells try to fight SARS-CoV-2 by targeting a broad range of sites on the virus–beyond the key sites on the virus’s spike protein. By attacking the virus from many angles, the body has the tools to potentially recognize different SARS-CoV-2 variants.

The new research, published January 27, 2021 in Cell Report Medicine, is the most detailed analysis so far of which proteins on SARS-CoV-2 stimulate the strongest responses from the immune system’s “helper” CD4+ T cells and “killer” CD8+ T cells.

“We are now armed with the knowledge of which parts of the virus are recognized by the immune system,” says LJI Professor Alessandro Sette, Dr. Biol. Sci., who co-led the new study with LJI Instructor Alba Grifoni, Ph.D.

Sette and Grifoni have led research into immune responses to the virus since the beginning of the pandemic. Their previous studies, co-led by members of the LJI Coronavirus Task Force, shows that people can have a wide range of responses to the virus–some people have strong immune responses and do well. Others have disjointed immune responses and are more likely to end up in the hospital.

As COVID-19 vaccines reach more people, LJI scientists are keeping an eye on how different people build immunity to SARS-CoV-2. They are also studying how T cells could combat different variants of SARS-CoV-2. This work takes advantage of the lab’s expertise in predicting and studying T cell responses to viruses such as dengue and Zika.

“This is even more important with COVID-19 because it is a global pandemic, so we need to account for immune responses in different populations,” says Grifoni.

The immune system is very flexible. By re-scrambling genetic material, it can make T cells that respond to a huge range of targets, or epitopes, on a pathogen. Some T cell responses will be stronger against some epitopes than others. Researchers call the targets that prompt a strong immune cells response “immunodominant.”

For the new study, the researchers examined T cells from 100 people who had recovered from SARS-CoV-2 infection. They then took a close look at the genetic sequence of the virus to separate the potential epitopes from the epitopes that these T cells would actually recognize.

Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone. In fact, T cells can recognize dozens of epitopes on SARS-CoV-2, and these immunodominant sites also change from person to person. On average, each study participant had the ability to recognize about 17 CD8+ T cells epitopes and 19 CD4+ T cell epitopes.

This broad immune system response serves a few purposes. The new study shows that while the immune system often mounts a strong response against a particular site on the virus’s “spike” protein called the receptor binding domain, this region is actually not as good at inducing a strong response from CD4+ helper T cells.

Without a strong CD4+ T cell response, however, people may be slow to mount the kind of neutralizing immune response that quickly wipes out the virus. Luckily, the broad immune response comes in handy, and most people have immune cells that can recognize sites other than the receptor binding domain.

Among the many epitopes they uncovered, the researchers identified several additional epitopes on the SARS-CoV-2 spike protein. Grifoni says this is good news. By targeting many vulnerable sites on the spike protein, the immune system would still be able to fight infection, even if some sites on the virus change due to mutations.

“The immune response is broad enough to compensate for that,” Grifoni says.

Since the announcement of the fast-spreading UK variant of SARS-CoV-2 (called SARS-CoV-2 VUI 202012/01), the researchers have compared the mutated sites on that virus to the epitopes they found. Sette notes that the mutations described in the UK variant for the spike protein affect only 8% of the epitopes recognized by CD4+ T cells in this study, while 92% of the responses is conserved.

Sette emphasized that the new study is the results of months of long hours and international collaboration between labs at LJI; the University of California, San Diego; and researcher’s at Australia’s Murdoch University. “This was a tremendous amount of work, and we were able to do it really fast because of our collaborations,” he says.

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The study, “Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases,” was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (AI42742 ,75N9301900065 and 75N93019C00001), the National Institutes of Health (U01 CA260541-01, AI135078, and AI036214); UCSD T32s (AI007036 and AI007384), the Jonathan and Mary Tu Foundation and the University of Genoa, Italy.

Additional study authors include first author Alison Tarke, John Sidney, Conner Kidd, Jennifer M. Dan, Sydney I. Ramirez, Esther Dawen Yu, Jose Mateus, Ricardo da Silva Antunes, Erin Moore, Paul Rubiro, Nils Methot, Elizabeth Phillips, Simon Mallal, April Frazier, Stephen A. Rawlings, Jason A. Greenbaum, Bjoern Peters, Davey M. Smith, Shane Crotty and Daniela Weiskopf.

DOI:10.1016/j.xcrm/2021/100202

About La Jolla Institute for Immunology

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.

“We are now armed with the knowledge of which parts of the virus are recognized by the immune system,” says LJI Professor Alessandro Sette, Dr. Biol. Sci., who co-led the new study with LJI Instructor Alba Grifoni, Ph.D.

Source: https://bioengineer.org/t-cells-can-mount-attacks-against-many-sars-cov-2-targets-even-on-new-virus-variant/

t-cells-can-mount-attacks-against-many-sars-cov-2-targets–even-on-new-virus-variant

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Trial of existing antibiotic for treating Staphylococcus aureus Bacteremia begins

NIH-supported trial will test Dalbavancin in hospitalized adultsCredit: NIAID A clinical trial to test the antibiotic dalbavancin for safety and

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A clinical trial to test the antibiotic dalbavancin for safety and efficacy in treating complicated Staphylococcus aureus (S. aureus) bacteremia has begun. The trial will enroll 200 adults hospitalized with complicated S. aureus infection at approximately 20 trial sites around the United States. The trial is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

S. aureus is a leading cause of antibiotic-resistant infection. S. aureus infections led to nearly 20,000 deaths in 2017 in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC). This bacterium is of particular concern in healthcare-associated infections. S. aureus bacteremia–an infection of the blood–often requires inserting a central intravenous (IV) catheter to deliver long courses of antibiotics, an invasive procedure that can involve long-term care in healthcare facilities.

“As antibiotic-resistant infections become more widespread, better and easier treatment regimens are needed to ease the burden on both healthcare providers and patients,” said NIAID Director Anthony S. Fauci, M.D. “By investigating existing antibiotics for their action on a broader array of bacterial infections, we may be able to generate new treatment regimens more efficiently.”

The antibiotic dalbavancin has strong activity against gram-positive bacteria, including methicillin-resistant S. aureus, which suggests it could be an effective treatment for S. aureus bacteremia. Dalbavancin is currently FDA-approved in the United States for treating acute bacterial skin and skin structure infections, including those caused by S. aureus. If the two-dose regimen being tested in this trial proves effective, it could lead to a shorter, less invasive treatment for S. aureus bacteremia that does not require an indwelling IV access for daily therapy.

The Phase 2b trial is being conducted by the NIAID-funded Antibacterial Resistance Leadership Group (ARLG) under the leadership of Thomas Holland, M.D., of Duke University (Durham, North Carolina.) It is called the “Dalbavancin as an Option for Treatment of S. aureus Bacteremia (DOTS)” trial. Patients who have stabilized after initial treatment of their bacteremia will be eligible for enrollment in this study.

“Dalbavancin is appealing as a potential option for treatment of these serious S. aureus infections, and we need high quality data to find out if it works,” said Dr. Holland, “This trial will provide clinicians and patients with that data.”

One hundred participants will be randomized to receive the standard of care for complicated infections, including appropriate antibiotics, and 100 participants will receive two doses of dalbavancin intravenously. The doses will be given one week apart. Most participants receiving dalbavancin will be given 1500 milligrams (mg) per dose. Participants with signs of kidney dysfunction will be given 1125 mg per dose. All participants will be followed for approximately 70 days after enrollment, and up to six months if they have vertebral osteomyelitis, an infection of the vertebrae.

At the end of the trial, multiple patient outcomes will be assessed: survival; additional complications (such as relapse) or clinical failures; drug-related adverse events; and overall quality of life. The therapeutic regimen will have met the primary endpoint of the trial if participants who received dalbavancin fare better on these metrics than those who received the current standard of care. This trial could validate a dalbavancin regimen of only one dose a week for two weeks, compared to daily doses administered intravenously for four to six weeks with the current standard of care.

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The ARLG is a clinical research consortium working to reduce the impact of antimicrobial resistance. It is funded through NIH grant UM1AI104681. For more information about this trial, visit ClinicalTrials.gov and search identifiers NCT04775953.

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NIAID conducts and supports research–at NIH, throughout the United States, and worldwide–to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIH…Turning Discovery Into Health®

Source: https://bioengineer.org/trial-of-existing-antibiotic-for-treating-staphylococcus-aureus-bacteremia-begins/

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Metabolite fumarate can reveal cell damage: New method to generate fumarate for MRI

Researchers find new technique for rapid hyperpolarization and purification of fumarate in aqueous solution; obstacles involving the use of parahydrogen

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Researchers find new technique for rapid hyperpolarization and purification of fumarate in aqueous solution; obstacles involving the use of parahydrogen overcome

A promising new concept published by an interdisciplinary research team in “Proceedings of the National Academy of Sciences” (PNAS) paves the way for major advances in the field of magnetic resonance imaging (MRI). Their new technique could significantly simplify hyperpolarized MRI, which developed around 20 years ago for observing metabolic processes in the body. The proposal involves the hyperpolarization of the metabolic product fumarate using parahydrogen and the subsequent purification of the metabolite. “This technique would not only be simpler, but also much cheaper than the previous procedure,” said leader of the project Dr. James Eills, a member of the research team of Professor Dmitry Budker at Johannes Gutenberg University Mainz (JGU) and the Helmholtz Institute Mainz (HIM). Also participating in the project were scientists from the fields of chemistry, biotechnology, and physics at TU Darmstadt, TU Kaiserslautern, the University of California Berkeley in the United States, the University of Turin in Italy, and the University of Southampton in England.

Fumarate is a key biosensor for hyperpolarized imaging

The potential applications of MRI are hindered by its low sensitivity and the technique is essentially limited to observing water molecules in the body. Researchers are therefore constantly working on different ways of improving MRI. A major breakthrough was achieved around 20 years ago when hyperpolarized magnetic resonance imaging was first developed: Because hyperpolarized molecules emit significantly stronger MRI signals, substances that are only present in low concentrations in the body can also be visualized. By hyperpolarizing biomolecules and introducing them in patients, it is possible to track metabolism in real time, thus providing doctors with much more information.

Hyperpolarized fumarate is a promising biosensor for the imaging of metabolic processes. Fumarate is a metabolite of the citric acid cycle that plays an important role in the energy production of living beings. For imaging purposes, the fumarate is tagged with carbon-13 as the atomic nuclei of this isotope can be hyperpolarized. Dynamic nuclear polarization is the current state-of-the-art method for hyperpolarizing fumarate, but this is expensive and relatively slow. The equipment required costs one to two million euros. “Dynamic nuclear polarization is very difficult to use in everyday clinical practice due to the related high costs and technical complexity. Using parahydrogen, we are able to hyperpolarize this important biomolecule in a cost-effective and convenient way,” said Dr. Stephan Knecht of TU Darmstadt, the first author of the published article.

A new method to hyperpolarize and purify fumarate for subsequent use as a biosensor

The research team led by Dr. James Eills has already been working on this concept for some time. “We have made a significant breakthrough as our approach is not only cheap, but also fast and easy to handle,” emphasized Eills. However, parahydrogen-induced polarization, or PHIP for short, also has its disadvantages. The low level of polarization and the large number of unwanted accompanying substances are particularly problematic in the case of this chemistry-based technique. Among other things, transferring the polarization from parahydrogen into fumarate requires a catalyst, which remains in the reaction fluid just like other reaction side-products. “The chemical contaminants must be removed from the solution so it is biocompatible and can be injected in living beings. This is essential if we think about the future clinical translation of this hyperpolarized biosensor,” said Dr. Eleonora Cavallari, a physicist from the Department of Molecular Biotechnology and Health Sciences in Turin.

The solution to this problem is to purify the hyperpolarized fumarate through precipitation. The fumarate then takes the form of a purified solid and can be redissolved at the desired concentration later. “This means we have a product from which all toxic substances have been removed so that it can readily be used in the body,” added Dr. James Eills. In addition, compared to previous experiments with PHIP, the polarization is increased to remarkable 30 to 45 percent. Preclinical studies have already shown that hyperpolarized fumarate imaging is a suitable method of monitoring how tumors respond to therapy as well as for imaging acute kidney injuries or the effects of myocardial infarction. This new way of producing hyperpolarized fumarate should greatly accelerate preclinical studies and bring this technology to more laboratories.

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Hyperpolarized fumarate is a promising biosensor for the imaging of metabolic processes. Fumarate is a metabolite of the citric acid cycle that plays an important role in the energy production of living beings. For imaging purposes, the fumarate is tagged with carbon-13 as the atomic nuclei of this isotope can be hyperpolarized. Dynamic nuclear polarization is the current state-of-the-art method for hyperpolarizing fumarate, but this is expensive and relatively slow. The equipment required costs one to two million euros. “Dynamic nuclear polarization is very difficult to use in everyday clinical practice due to the related high costs and technical complexity. Using parahydrogen, we are able to hyperpolarize this important biomolecule in a cost-effective and convenient way,” said Dr. Stephan Knecht of TU Darmstadt, the first author of the published article.

Source: https://bioengineer.org/metabolite-fumarate-can-reveal-cell-damage-new-method-to-generate-fumarate-for-mri/

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Skoltech researchers propose a new data-driven tool to better understand startups

Credit: Malyy et al., 2021 Skoltech researchers used Google Trends’ Big Data ensuing from human interactions with the Internet to

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Skoltech researchers used Google Trends’ Big Data ensuing from human interactions with the Internet to develop a new methodology – a tool and a data source – for analyzing and researching the growth of startups. A paper reporting these important findings was published in technology management journal, Technological Forecasting and Social Change.

Startups and high-growth technology-based ventures they transform into are regarded as the key drivers of economic development, innovation, and job creation on the national and global level. However, despite their crucial importance for the economy and high interest from researchers and policy-makers, startups display growth patterns that are difficult to analyze. These fragile, early-stage private businesses, which may quickly scale up, do not have time, interest, or obligation to share much data about what they achieved, when, or how. Thus, to outside observers, startups look like “black boxes” whose progress can hardly be assessed due to a lack of objective information.

Maksim Malyy, a PhD student from the Skoltech Center for Entrepreneurship and Innovation (CEI), has been intrigued by this problem since he worked in a startup accelerator in St. Petersburg before joining Skoltech. Looking into theoretical and practical aspects of the problem for the last three years, Maksim, his supervisor, professor Zeljko Tekic, and Skoltech assistant professor Tatiana Podladchikova came up with valuable insights on how to deal with the data scarcity problem in studying startups. Some of their findings were published in the paper.

Maksim explains why this research is so important: We demonstrate that web-search traffic information, in particular Google Trends data, can serve as a valuable source of high-quality data for analyzing the advancement of startups and growth-oriented technology-based new ventures they evolve into. We analyzed a large and transparently selected set of US based companies and showed the existence of a strong correlation between the curves based on Google searches by company name and those depicting valuations achieved through a series of investment rounds.

According to the authors, this correlation enables using Google Trends data as a proxy measure of growth instead of non-public and rarely available measures like sales, employee and market share growth. Google Trends data, which are public, easy to collect and available for almost any company since its inception, can help in building more accurate and even real-time data-driven growth paths for startups. With these evolution curves, one could revisit some old answers, ask new questions, and come up with more solid concepts, theories, and predictions.

Maksim believes that this study has strong implications for start-up research: Our findings suggest that for startups, especially thriving unicorns or B2C digital platforms, the proposed approach may become an equivalent of an X-ray scan, offering a cheap, easy, and non-invasive way to understand the workings of a technology-based new venture.

By way of comment, professor Tekic and professor Podladchikova cite a report by one of the reviewers: “I think this paper will stand the test of time and be useful for many years to come. It truly is a fascinating study.”

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https://www.skoltech.ru/en/2021/04/skoltech-researchers-propose-a-new-data-driven-tool-to-better-understand-startups/

Maksim believes that this study has strong implications for start-up research: Our findings suggest that for startups, especially thriving unicorns or B2C digital platforms, the proposed approach may become an equivalent of an X-ray scan, offering a cheap, easy, and non-invasive way to understand the workings of a technology-based new venture.

Source: https://bioengineer.org/skoltech-researchers-propose-a-new-data-driven-tool-to-better-understand-startups/

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